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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
2.
J Am Heart Assoc ; 8(7): e011662, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30922146

RESUMO

Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of ß-hydroxy ß-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.

3.
N Engl J Med ; 380(11): 1022-1032, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30865796

RESUMO

BACKGROUND: Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy. METHODS: We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks. RESULTS: The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy. CONCLUSIONS: In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).


Assuntos
LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Idoso , Apolipoproteínas B/sangue , Proteína C-Reativa/análise , Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Resultado do Tratamento
4.
Clin Transl Sci ; 10(6): 455-469, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28795506

RESUMO

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0-8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25-0.86), 300-500 mg D-4F effectively halved HII: 1.35-0.57 and 1.22-0.63, respectively (P < 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function.


Assuntos
Apolipoproteína A-I/administração & dosagem , Apolipoproteína A-I/uso terapêutico , Inflamação/tratamento farmacológico , Lipoproteínas HDL/metabolismo , Administração Oral , Adulto , Idoso , Apolipoproteína A-I/efeitos adversos , Apolipoproteína A-I/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo
6.
Pharmacotherapy ; 34(3): 227-39, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24734312

RESUMO

STUDY OBJECTIVE: To characterize the effects of two doses (10 and 60 mg) of lomitapide­a microsomal triglyceride transfer protein inhibitor approved as adjunct treatment to lower low-density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia­on the pharmacokinetics of several lipid-lowering therapies: atorvastatin, simvastatin, rosuvastatin, fenofibrate, ezetimibe, and niacin. DESIGN: Two prospective open-label studies (study 1 and study 2). SETTING: Two clinical research units. SUBJECTS: A total of 130 healthy volunteers (114 subjects in study 1 and 16 subjects in study 2). INTERVENTION: In study 1, subjects were enrolled sequentially to one of the following eight open-label treatment arms (probe drug + lomitapide): atorvastatin 20 mg + lomitapide 10 mg, atorvastatin 20 mg + lomitapide 60 mg, simvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 60 mg, fenofibrate 145 mg + lomitapide 10 mg, ezetimibe 10 mg + lomitapide 10 mg, and extended-release niacin 1000 mg + lomitapide 10 mg. Study 2 consisted of the ninth treatment arm: simvastatin 40 mg + lomitapide 60 mg. Subjects received one dose of the probe drug on the morning of day 1. On days 2­7, subjects took their dose of lomitapide once/day in the morning. On day 8, subjects received one dose of lomitapide simultaneously with the same probe drug they took on day 1. Subjects returned 1 week later (day 15) for a final visit to check safety laboratory parameters. MEASUREMENTS AND MAIN RESULTS: A full pharmacokinetic profile was performed for the probe drug on day 1 and day 8 (after 7 days of dosing with lomitapide [i.e., at steady state]). Pharmacokinetic parameters were calculated from the plasma concentration-time data for each day by using noncompartmental methods. Analysis of variance was applied to the ln-transformed maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0­t (AUC0­t) values, and ratios of the means were compared for day 8 versus day 1. Lomitapide increased exposure to the statin medications. The percent least squares means ratios (LSMR%) (90% confidence intervals [CIs]) for AUC0­t of the statin medications with lomitapide at the 60 mg dose were as follows: 129 (115­144) for the sum of the active atorvastatin moieties, 168 (139­203) for simvastatin acid, and 132 (112­157) for rosuvastatin. The LSMR% (90% CI) for Cmax was 138 (120­160) for the sum of the active atorvastatin moieties, 157 (133­186) for simvastatin acid, and 104 (82­32) for rosuvastatin. The LSMRs were not appreciably altered for the other probe drugs. CONCLUSION: This study shows that lomitapide is a weak inhibitor of CYP3A4 and increased the exposure of statin medications. Careful monitoring of adverse events of CYP3A4-metabolized statins should be used when initiating therapy with lomitapide.


Assuntos
Anticolesterolemiantes/farmacocinética , Benzimidazóis/farmacocinética , Proteínas de Transporte/antagonistas & inibidores , Interações de Medicamentos , Hipercolesterolemia/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Benzimidazóis/administração & dosagem , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Interações de Medicamentos/fisiologia , Quimioterapia Combinada , Feminino , Humanos , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
7.
Lancet ; 381(9860): 40-6, 2013 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-23122768

RESUMO

BACKGROUND: Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. METHODS: We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. FINDINGS: 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. INTERPRETATION: Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FUNDING: FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.


Assuntos
Benzimidazóis/uso terapêutico , Proteínas de Transporte/antagonistas & inibidores , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Benzimidazóis/efeitos adversos , LDL-Colesterol/sangue , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino
8.
J Lipid Res ; 52(1): 136-42, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20971975

RESUMO

Treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone significantly reduced fasting insulin and high-sensitivity C-reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was significantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone significantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was unrelated to effects on apoA-I, instead being related to the change in the metabolism of apoA-II.


Assuntos
Lipoproteínas HDL/sangue , Síndrome Metabólica/sangue , Tiazolidinedionas/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/sangue , Apolipoproteína A-II/sangue , Proteína C-Reativa/análise , HDL-Colesterol/sangue , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Rosiglitazona , Tiazolidinedionas/administração & dosagem
9.
Metab Syndr Relat Disord ; 7(2): 143-50, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19422140

RESUMO

BACKGROUND: The use of chromium-containing dietary supplements is widespread among patients with type 2 diabetes. Chromium's effects in patients at high risk for developing diabetes, especially those with metabolic syndrome, is unknown. The objective of this study was to determine the effects of chromium picolinate (CrPic) on glucose metabolism in patients with metabolic syndrome. METHOD: A double-blind, placebo-controlled, randomized trial was conducted at a U.S. academic medical center. Sixty three patients with National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)-defined metabolic syndrome were included. The primary end point was a change in the insulin sensitivity index derived from a frequently sampled intravenous glucose tolerance test. Prespecified secondary end points included changes in other measurements of glucose metabolism, oxidative stress, fasting serum lipids, and high sensitivity C-reactive protein. RESULTS: After 16 weeks of CrPic treatment, there was no significant change in insulin sensitivity index between groups (P = 0.14). However, CrPic increased acute insulin response to glucose (P 0.02). CrPic had no significant effect on other measures of glucose metabolism, body weight, serum lipids, or measures of inflammation and oxidative stress. CONCLUSION: CrPic at 1000 microg/day does not improve key features of the metabolic syndrome in obese nondiabetic patients.


Assuntos
Glicemia/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Obesidade/complicações , Ácidos Picolínicos/uso terapêutico , Centros Médicos Acadêmicos , Adulto , Idoso , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Feminino , Teste de Tolerância a Glucose , Humanos , Mediadores da Inflamação/sangue , Insulina/sangue , Lipídeos/sangue , Masculino , Adesão à Medicação , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Philadelphia , Ácidos Picolínicos/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
10.
Arterioscler Thromb Vasc Biol ; 29(1): 140-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18988892

RESUMO

OBJECTIVE: The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). METHODS AND RESULTS: Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (-38%, P=0.002) and triglyceride (-23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (-12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II. CONCLUSIONS: Activation of PPAR-alpha with LY518674 (100 microg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.


Assuntos
Apolipoproteína A-I/sangue , Síndrome Metabólica/sangue , PPAR alfa/agonistas , Propionatos/farmacologia , Triazóis/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína A-I/genética , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Deutério , Método Duplo-Cego , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Placebos , Triglicerídeos/sangue , Adulto Jovem
11.
J Am Coll Nutr ; 27(1): 65-74, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18460483

RESUMO

OBJECTIVE: Flaxseed is a rich source of alpha linolenic acid (ALA), fiber and lignans, making it a potentially attractive functional food for modulating cardiovascular risk. We studied the effects of flaxseed on markers of cardiovascular risk in hypercholesterolemic adults. METHODS: Sixty-two men and post-menopausal women with pre-study low density lipoprotein cholesterol (LDL-C) between 130 and 200 mg/dl were randomized to 40g/day of ground flaxseed-containing baked products or matching wheat bran products for 10 weeks while following a low fat, low cholesterol diet. Fasting lipoproteins, measures of insulin resistance, inflammation, oxidative stress, and safety were assessed at 0, 5 and 10 weeks. RESULTS: Flaxseed was well-tolerated, and increased serum levels of ALA (p < 0.001). Compared to wheat, flaxseed significantly reduced LDL-C at 5 weeks (-13%, p < 0.005), but not at 10 weeks (-7%, p = 0.07). Flaxseed reduced lipoprotein a (Lp[a]) by a net of 14% (p = 0.02), and reduced the homeostatic model assessment of insulin resistance (HOMA-IR) index by 23.7% (p = 0.03) compared to wheat at 10 weeks, but did not affect markers of inflammation (IL-6, Hs-CRP) or oxidative stress (ox LDL, urinary isoprostanes) at any time points. In men, flaxseed reduced HDL-C concentrations by a net of 16% (p = 0.03) and 9% (p = 0.05) at 5 and 10 weeks, respectively. CONCLUSIONS: Ground flaxseed has a modest but short lived LDL-C lowering effect, yet reduces Lp(a) and improves insulin sensitivity in hyperlipidemic adults. The HDL-C lowering effect of flaxseed in men warrants additional study.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta com Restrição de Gorduras , Linho , Hipercolesterolemia/dietoterapia , Idoso , Biomarcadores , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Fatores de Tempo , Resultado do Tratamento , Ácido alfa-Linoleico/administração & dosagem , Ácido alfa-Linoleico/sangue
12.
N Engl J Med ; 356(2): 148-56, 2007 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-17215532

RESUMO

BACKGROUND: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients. METHODS: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study. RESULTS: All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%. CONCLUSIONS: Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.


Assuntos
Benzimidazóis/administração & dosagem , Proteínas de Transporte/antagonistas & inibidores , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Alanina Transaminase/sangue , Apolipoproteínas B/sangue , Benzimidazóis/efeitos adversos , LDL-Colesterol/biossíntese , LDL-Colesterol/sangue , Terapia Combinada , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/dietoterapia , Fígado/efeitos dos fármacos , Masculino
13.
Arterioscler Thromb Vasc Biol ; 26(1): 182-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16284192

RESUMO

OBJECTIVE: The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn). METHODS AND RESULTS: Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance. CONCLUSIONS: In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.


Assuntos
Adiponectina/sangue , Aterosclerose/tratamento farmacológico , HDL-Colesterol/sangue , Hipoglicemiantes/administração & dosagem , Síndrome Metabólica/tratamento farmacológico , Tiazolidinedionas/administração & dosagem , Adulto , Idoso , Aterosclerose/sangue , Aterosclerose/imunologia , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , LDL-Colesterol/sangue , Feminino , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/imunologia , Pessoa de Meia-Idade , Pioglitazona , Triglicerídeos/sangue
14.
Arterioscler Thromb Vasc Biol ; 26(3): 624-30, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16357312

RESUMO

BACKGROUND: PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome. METHODS AND RESULTS: We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus -1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (-6% versus +4%; P=0.009), C-reactive protein (-32% versus +36%, P=0.002), interleukin (IL)-6 (-22% versus +4%, P<0.001), and soluble tumor-necrosis factor-alpha receptor-2 (-5% versus +7%, P<0.001). CONCLUSIONS: These findings suggest that rosiglitazone, presumably through its PPAR-gamma agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.


Assuntos
HDL-Colesterol/sangue , Hipoglicemiantes/administração & dosagem , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/imunologia , Tiazolidinedionas/administração & dosagem , Adiponectina/sangue , Adolescente , Adulto , Idoso , Apolipoproteínas B/sangue , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Resistência à Insulina , Interleucina-6/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , PPAR gama/agonistas , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Resistina/sangue , Rosiglitazona , Tiazolidinedionas/efeitos adversos
15.
N Engl J Med ; 350(15): 1505-15, 2004 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-15071125

RESUMO

BACKGROUND: Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels. METHODS: We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks. RESULTS: Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort. CONCLUSIONS: In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.


Assuntos
Anticolesterolemiantes/uso terapêutico , Proteínas de Transporte/antagonistas & inibidores , HDL-Colesterol/sangue , Glicoproteínas , Quinolinas/uso terapêutico , Adulto , Idoso , Apolipoproteína A-I/sangue , Apolipoproteína A-II/sangue , Atorvastatina , Proteínas de Transferência de Ésteres de Colesterol , LDL-Colesterol/sangue , Quimioterapia Combinada , Feminino , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirróis/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Método Simples-Cego , Triglicerídeos/sangue
16.
Nutr Rev ; 62(1): 18-27, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14995053

RESUMO

Flaxseed has recently gained attention in the area of cardiovascular disease primarily because it is the richest known source of both alpha-linolenic acid (ALA) and the phytoestrogen, lignans, as well as being a good source of soluble fiber. Human studies have shown that flaxseed can modestly reduce serum total and low-density lipoprotein cholesterol concentrations, reduce postprandial glucose absorption, decrease some markers of inflammation, and raise serum levels of the omega-3 fatty acids, ALA and eicosapentaenoic acid. Data on the antiplatelet, antioxidant, and hypotensive effects of flaxseed, however, are inconclusive. More research is needed to define the role of this functional food in reducing cardiovascular risk.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Linho/química , Animais , Anti-Inflamatórios/administração & dosagem , Colesterol/sangue , LDL-Colesterol/sangue , Fibras na Dieta/administração & dosagem , Fibras na Dieta/farmacologia , Ácidos Graxos Ômega-3/sangue , Alimentos Orgânicos , Humanos , Hipolipemiantes/administração & dosagem , Lignanas/administração & dosagem , Lignanas/farmacologia , Fatores de Risco , Ácido alfa-Linoleico/administração & dosagem , Ácido alfa-Linoleico/sangue
17.
Curr Cardiol Rep ; 5(6): 488-92, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14558992

RESUMO

Physical activity is an important component of weight control, and is widely recommended to prevent and treat obesity-related complications such as diabetes and coronary heart disease (CHD). Although the cardiovascular benefits of increased physical activity are likely multifactorial, much of the attention has been focused on the known high-density lipoprotein (HDL) cholesterol-raising properties of regular physical activity. Physical activity, however, can also reliably lower triglycerides and favorably affect both low-density lipoprotein (LDL) and HDL particle sizes. Limited data on resistance exercise suggest that this type of physical activity may reduce LDL cholesterol. Although these lipid effects are modest and variable, they are likely to be particularly important in reducing the morbidity and mortality from CHD on a population level, and may be especially important in patients with atherogenic dyslipidemia.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Lipoproteínas/metabolismo , Atividade Motora/fisiologia , Humanos
18.
JAMA ; 290(6): 765-72, 2003 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-12915429

RESUMO

CONTEXT: Herbal extracts from Commiphora mukul (guggul) have been widely used in Asia as cholesterol-lowering agents, and their popularity is increasing in the United States. Recently, guggulsterones, the purported bioactive compounds of guggul, have been shown to be potent antagonists of 2 nuclear hormone receptors involved in cholesterol metabolism, establishing a plausible mechanism of action for the hypolipidemic effects of these extracts. However, there are currently no published safety or efficacy data on the use of guggul extracts in Western populations. OBJECTIVE: To study the short-term safety and efficacy of 2 doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia eating a typical Western diet. DESIGN: Double-blind, randomized, placebo-controlled trial using a parallel design, conducted March 2000-August 2001. PARTICIPANTS AND SETTING: A total of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia in the Philadelphia, Pa, metropolitan area. INTERVENTION: Oral, 3 times daily doses of standard-dose guggulipid (1000 mg), high-dose guggulipid (2000 mg), or matching placebo. MAIN OUTCOME MEASURES: Percentage change in levels of directly measured low-density lipoprotein cholesterol (LDL-C) after 8 weeks of therapy. Secondary outcome measures included levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and directly measured very low-density lipoprotein cholesterol (VLDL-C), as well as adverse events reports and laboratory safety measures including electrolyte levels and hepatic and renal function. RESULTS: Compared with participants randomized to placebo (n = 36), in whom levels of LDL-C decreased by 5%, both standard-dose guggulipid (n = 33) and high-dose guggulipid (n = 34) raised levels of LDL-C by 4% (P =.01 vs placebo) and 5% (P =.006 vs placebo), respectively, at 8 weeks, for a net positive change of 9% to 10%. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggulipid in the intention-to-treat analysis. While guggulipid was generally well tolerated, 6 participants treated with guggulipid developed a hypersensitivity rash compared with none in the placebo group. CONCLUSIONS: Despite plausible mechanisms of action, guggulipid did not appear to improve levels of serum cholesterol over the short term in this population of adults with hypercholesterolemia, and might in fact raise levels of LDL-C. Guggulipid also appeared to cause a dermatologic hypersensitivity reaction in some patients.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pregnenodionas/uso terapêutico , Commiphora , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Gomas Vegetais
19.
Am J Clin Nutr ; 76(5): 1126-37, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12399289

RESUMO

BACKGROUND: Soy isoflavones are being evaluated as chemopreventive agents for breast and other cancers. OBJECTIVE: The objective was to perform safety and pharmacokinetic studies of purified unconjugated isoflavone preparations containing genistein, daidzein, and glycitein in postmenopausal women. DESIGN: Twenty-four healthy postmenopausal women ingested a single dose of 1 of 2 purified (from soybeans) isoflavone preparations that delivered a genistein dose of 2, 4, 8, or 16 mg/kg body wt. These doses were higher than those previously administered to human females. Toxicity studies were performed 24 h and 3, 6, 14, and 30 d after isoflavone administration. Kinetic studies were performed during the first 24 h. RESULTS: We observed a 7% decrease in systolic and diastolic blood pressure and a 32% decrease in the neutrophil count 24 h after treatment with formulation A. Isolated episodes of nausea, pedal edema, and breast tenderness were judged to be possibly related to the study treatment. The terminal plasma half-lives for free genistein, daidzein, and glycitein averaged 3.8, 7.7, and 3.4 h, respectively. The terminal pseudo half-lives for total genistein and total daidzein in plasma averaged 10.1 and 10.8 h, respectively. The estimated bioavailabilities of both total genistein and total daidzein from each of the 2 formulations were not significantly different. CONCLUSIONS: A single-dose administration of purified unconjugated isoflavones at amounts that exceed normal dietary intakes had minimal clinical toxicity in healthy postmenopausal women. The pharmacokinetic data suggest that chronic dosing at 12-24-h intervals would not lead to progressive accumulation of these isoflavones.


Assuntos
Isoflavonas/administração & dosagem , Isoflavonas/farmacocinética , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo , Soja/química , Idoso , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Genisteína/sangue , Genisteína/urina , Meia-Vida , Humanos , Isoflavonas/efeitos adversos , Isoflavonas/sangue , Isoflavonas/farmacologia , Isoflavonas/urina , Pessoa de Meia-Idade
20.
Am J Clin Nutr ; 75(1): 126-36, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11756070

RESUMO

BACKGROUND: Soy isoflavones are potential cancer chemoprevention treatments. OBJECTIVE: We conducted safety studies of purified unconjugated genistein, daidzein, and glycitein, and defined pharmacokinetic parameters for their absorption and metabolism. DESIGN: Thirty healthy men ingested a single dose of 1 of 2 isoflavone preparations purified from soy. The delivered doses of genistein (1, 2, 4, 8, or 16 mg/kg body wt) were higher than those previously administered to humans. Formulation A was composed of 90 +/- 5% genistein, 10% daidzein, and 1% glycitein. Formulation B was composed of 43% genistein, 21% daidzein, and 2% glycitein. RESULTS: We observed no clinically significant behavioral or physical changes after treatment. We observed elevations in lipoprotein lipase and hypophosphatemia that were possibly related to the treatment but that were associated with no clinical toxicity. Considerable quantities of isoflavones were excreted in urine as conjugates. The terminal elimination rate, elimination half-life, area under the curve, maximum plasma concentration, apparent systemic clearance, and volume of distribution were estimated for genistein and daidzein. The mean elimination half-lives with both formulations were 3.2 h for free genistein and 4.2 h for free daidzein. The mean pseudo half-lives were 9.2 h for total genistein and 8.2 h for total daidzein. CONCLUSIONS: Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manyfold resulted in minimal clinical toxicity. Genistein and daidzein (free and total) were rapidly cleared from plasma and excreted in urine.


Assuntos
Anticarcinógenos/farmacocinética , Genisteína/farmacocinética , Isoflavonas/farmacocinética , Soja , Adulto , Anticarcinógenos/sangue , Estrogênios não Esteroides/sangue , Estrogênios não Esteroides/farmacocinética , Genisteína/sangue , Meia-Vida , Humanos , Isoflavonas/efeitos adversos , Isoflavonas/sangue , Masculino
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